Abstract The standard approach to TB control relies on detection and treatment of Mycobacterium tuberculosis (Mtb) disease. This approach may have limited effectiveness in areas where the high burden of TB leads to high levels of transmission. To curb the TB epidemic, new cases must be prevented. Preventive therapy is an effective intervention as it reduces the risk of progression to disease by 65 ? 85% in both HIV-positive (HIV+) and negative (HIV-) individuals. A monumental challenge still remains: one-quarter of the world's population is infected with Mtb. Treating all individuals with LTBI is not feasible: a strategy to identify those at highest risk for progression to TB is required. Contacts who are newly infected experience a period of high risk for progressive disease that lasts about 2 to 3 yrs. Our recent cohort study in urban Uganda measured the annual rate of Mtb infection in the community as close to 10%/yr. For most individuals with latent Mtb infection (LTBI), the timing of infection is unknown and biomarkers of recent infection would help identify persons at greatest risk for disease progression. A proteomic analysis of serum from TB household contacts who converted their tuberculin skin test (TST) identified a protein signature for new Mtb infection. Improving upon this signature and determining its use in the community to identify persons who recently developed LTBI would allow for targeted preventive therapy and ?halt Mtb transmission?. The overall hypothesis for this proposal is that serum/plasma biomarker signatures of new Mtb infection can identify HIV+ and HIV- adults in high Mtb transmission areas and targeting these individuals for preventive therapy will reduce TB and Mtb transmission in the community. There are 3 aims. Aim 1 will test and enhance a host protein signature as biomarker for new Mtb infection in HIV-infected and non-infected persons. We will use plasma collected in an ongoing TB household contact study in Kampala, Uganda in which TST-/IGRA- HIV+ and HIV- adults are enrolled and followed for IGRA/TST conversion. We will determine if serum cytokines enhance the predictive accuracy of this protein signature. Aim 2 will identify new Mtb infection in high risk environments in an urban African setting. GPS tracking technology will be used to trace and longitudinally map subjects to locate areas of high Mtb transmission, i.e. ?hot-spots?. Subjects will be enrolled and followed for IGRA/TST conversion every 3 months over 1 yr with serial sampling of plasma. Aim 3 will determine if the protein signature(s) developed in Aim 1 can identify new Mtb infections in the community. This project builds on more than 20 years of experience by this investigative team studying Mtb transmission in TB households and community in Kampala, Uganda, and host responses to Mtb infection and disease in HIV+ and HIV- persons. This proposal brings together expertise in Mtb epidemiology (Drs. Whalen, Kiwanuka, Joloba, Stein), immunology (Drs. Mayanja, Boom) and biomarker development (Drs. Bark, Paramithiotis) at CWRU, Makerere University, University of Georgia, and Caprion Inc.